A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke.

ABSTRACT: Mutations in the type 1 ryanodine receptor (RyR1), a Ca²⁺ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that an oxolinic acid-derivative RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1, Cpd1), effectively prevents and treats MH and heat stroke in several mouse models relevant to MH. Cpd1 reduces resting intracellular Ca²⁺, inhibits halothane- and isoflurane-induced Ca²⁺ release, suppresses caffeine-induced contracture in skeletal muscle, reduces sarcolemmal cation influx, and

SUBMITTER: Yamazawa T 

PROVIDER: S-EPMC8277899 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature